S282: A RANDOMIZED CONTROLLED CLINICAL TRIAL DEMONSTRATES THAT PLASMA FROM CONVALESCENT AND VACCINATED DONORS IMPROVES OUTCOME OF COVID-19 IN PATIENTS WITH HEMATOLOGICAL DISEASE, CANCER OR IMMUNOSUPPRESSION
Authors: C. Müller-Tidow, M. Janssen, U. Schäkel, J. Gall, A. Leo, P. Stelmach, J. Krisam, L. Baumann, J. Stermann, U. Merle, M. Zeier, M. A. Weigand, L. Bullinger, J.-F. Schrezenmeier, M. Bornhäuser, N. Alakel, O. Witzke, T. Wolf, M. J. Vehreschild, S. Schmiedel, M. M. Addo, F. Herth, M Kreutner, P.-R. Tepasse, B. Hertenstein, M. Hänel, A. Morgner, M. Kiehl, O. Hopfer, M.-A. Wattad, C. C. Schimanski, C Celik, T. Pohle, M. Ruhe, W. V. Kern, A Schmitt, M. Schmitt, P. Dreger, H.-M. Lorenz, M. Souto-Carneiro, N. Halama, S. Meuer, H.-G. Kräusslich, B. Müller, R. Bartenschlager, J. Klemmer, K. Kriegsmann, R. F. Schlenk, C. M. Denkinger
Journal: HemaSphere (2022)

Background: Therapy options are limited for COVID-19 patients with hematological disease, cancer, immunosuppression or advanced age. Even though no benefit was observed for convalescent plasma in unselected patients with COVID-19, retrospective data suggest that it could be effective in patients unable to mount a sufficient immune response upon SARS-CoV-2 infection. Plasma from vaccinated donors has not been systematically assessed for COVID-19 treatment. Aims: We conducted a randomized clinical trial to address plasma efficacy in patients at high risk for an adverse outcome. Methods: COVID-19 patients with confirmed SARS-CoV-2 infections and oxygen saturation <=94% were randomized (NCT05200754). Patients received convalescent or vaccinated SARS-CoV-2 plasma in two bags (238 - 337 ml plasma each) from different donors on day 1 and 2 (PLASMA) or standard of care (CONTROL). Randomization was stratified according to four clinical patient groups, hematological/solid cancer (group-1), treatment or disease associated immunosuppression (group 2), high risk disease by standard parameters (group-3) or age >=75 years (group-4). Mechanically ventilated patients were not eligible. Plasma was obtained from donors with high level neutralizing activity (titer >=1:80) either after SARS-CoV-2 infection (convalescent) or after vaccination with at least two doses of mRNA vaccines (vaccinated). Crossover for the control group was allowed at day 10. The primary endpoint was time to improvement as two points on a seven-point ordinal scale or live discharge from the hospital (IMPROVEMENT) with prespecified analyses of subgroups (Janssen M, et al. Trials 2020 Oct 6;21(1):828). Results: A total of 133 patients were randomized with 68 receiving PLASMA with a median age of 68 years (range 36-95) or CONTROL (n=65, of which n=10 (15.4%) crossed over at day 10) with a median age of 70 years (range 38-90). The distribution of the four predefined groups was group-1, n=53; group-2, n=18; group-3, n=35; and group-4, n=27. The intention to treat analysis revealed a non-significant shorter time to IMPROVEMENT for patients in PLASMA (median 12.5 days, 95%-CI [10; 16]) compared to patients in CONTROL (median 18 days, 95%-CI [11; 28]), hazard ratio 1.24, 95% confidence interval [0.83; 1.85], p=0.29). Overall, 27 patients died (PLASMA, n=12; CONTROL, n=15; p=0.80). Predefined subgroup analysis revealed a clinically significant benefit in patients with hematological malignancies, other cancers or immunosuppression (group-1, group-2, n=71). With a median time to improvement of 13 days (95%-CI [9; 19]) for PLASMA and 32 days (95%-CI [17; 57]) for CONTROL(HR 2.03, 95%-CI [1.17; 3.6], p=0.01). A sensitivity analysis revealed that IMPROVEMENT appeared to be seen even earlier with vaccinated (median 10 days, 95%-CI [8; 14]) compared to convalescent SARS-CoV-2 plasma (median 13 days, 95%-CI [6; 38]) and CONTROL. Within group-1 and group-2, six patients in PLASMA (18.2%) and 10 in CONTROL (28.6%) died. No significant differences in improvement were observed in group-3 and group-4 with a HR of 0.72 (95%-CI [0.41; 1.28], p=0.26). Within group-3 and group-4, six patients in PLASMA (18.8%) and five in CONTROL (16.7%) died. No previously unknown side effects of plasma therapy emerged within the trial. Image:Summary/Conclusion: Plasma from convalescent and particularly vaccinated donors improved outcome of COVID-19 patients with an underlying hematological disease /cancer or other reasons of impaired immune response. Plasma did not improve outcome in immune-competent patients with other risk factors and/or older age.